Insect strains have been genetically engineered for decreased capacity to reproduce and for inability to transmit disease-causing pathogens. Insects with such traits are not expected to replace native insect genotypes through the direct action of natural selection so there is a need to develop genetic drive mechanisms that will force these transgenes into native insect populations. A number of potential strategies for using specific drive mechanisms have been discussed, and preliminary population genetic models have been developed to assess the feasibility of certain strategies. There are numerous gaps in these assessments. The proposed research will develop a comprehensive modeling framework that can be used in determining the transgenic approaches that are most likely to successfully suppress specific insect-borne diseases in specific regions. A major focus will be the building of a spatially explicit stochastic model of vector population dynamics and genetics. This model will be coupled to models of disease epidemiology. The first model will be designed to fit the biology of Aedes aegypti and dengue virus (DV). Estimates of many relevant biological parameters are available from previous and ongoing research. Other parameters will be estimated from proposed experiments that will measure the fitness costs expected to be associated with insertion of transgenes, and the pattern of intra-genomic movement of loaded transposons. Specific transgenic manipulations that will be examined are: 1) insertion of conditional lethal alleles, 2) insertion of female-specific lethality alleles 3) engineered underdominance, 4) insertion of loaded autonomous transposons, 5) infection with transgenic Wolbachia strains. The potential for using novel transgenic manipulations will be examined with more general models. Results of the modeling work will predict, based on current biological data, which DV suppression strategies are expected to succeed under specific environmental conditions. The results will also indicate where future empirical research efforts should be focused to gain more precise and accurate estimates of critical biological parameters for Ae. aegypti. Interdisciplinary workshops will be held to ensure that the final model framework developed is flexible enough to be used by researchers working with malaria and other insect-borne diseases. A user-friendly form of the models as well as an accessible manual will be developed and placed on the internet.